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Peroxisome proliferator-activated receptor alpha plays a crucial role in behavioral repetition and cognitive flexibility in mice.

D'Agostino G, Cristiano C, Lyons DJ, Citraro R, Russo E, Avagliano C, Russo R, Raso GM, Meli R, De Sarro G, Heisler LK, Calignano A - Mol Metab (2015)

Bottom Line: Specifically, we observed that Ppar-α genetic perturbation promotes rewiring of cortical and hippocampal regions and a behavioral phenotype of cognitive inflexibility, perseveration and blunted responses to psychomimetic drugs.Furthermore, we demonstrate that the antipsychotic and autism spectrum disorder (ASD) medication risperidone ameliorates the behavioral profile of Ppar-α deficient mice.These results thereby reveal an unforeseen therapeutic application for a class of drugs currently in human use.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy ; Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, United Kingdom.

ABSTRACT

Background/objectives: Nuclear peroxisome proliferator activated receptor-α (PPAR-α) plays a fundamental role in the regulation of lipid homeostasis and is the target of medications used to treat dyslipidemia. However, little is known about the role of PPAR-α in mouse behavior.

Methods: To investigate the function of Ppar-α in cognitive functions, a behavioral phenotype analysis of mice with a targeted genetic disruption of Ppar-α was performed in combination with neuroanatomical, biochemical and pharmacological manipulations. The therapeutic exploitability of PPAR-α was probed in mice using a pharmacological model of psychosis and a genetic model (BTBR T + tf/J) exhibiting a high rate of repetitive behavior.

Results: An unexpected role for brain Ppar-α in the regulation of cognitive behavior in mice was revealed. Specifically, we observed that Ppar-α genetic perturbation promotes rewiring of cortical and hippocampal regions and a behavioral phenotype of cognitive inflexibility, perseveration and blunted responses to psychomimetic drugs. Furthermore, we demonstrate that the antipsychotic and autism spectrum disorder (ASD) medication risperidone ameliorates the behavioral profile of Ppar-α deficient mice. Importantly, we reveal that pharmacological PPAR-α agonist treatment in mice improves behavior in a pharmacological model of ketamine-induced behavioral dysinhibition and repetitive behavior in BTBR T + tf/J mice.

Conclusion: Our data indicate that Ppar-α is required for normal cognitive function and that pharmacological stimulation of PPAR-α improves cognitive function in pharmacological and genetic models of impaired cognitive function in mice. These results thereby reveal an unforeseen therapeutic application for a class of drugs currently in human use.

No MeSH data available.


Related in: MedlinePlus

Risperidone improves repetitive behavior in Ppar-α  mice. Effect of 7–10 days treatment with risperidone (0.01 mg/kg−1, IP) on marble burying behavior (A) and self-grooming (C). Re-appearance of the increased marble burying (B) and self-grooming behaviors (D) one week after treatment's suspension (3 months-old male mice n = 8–12; *p < 0.05 and **p < 0.01 vs wild type mice, &p < 0.05 vs Ppar-α −/− mice treated with vehicle; one-way ANOVA, followed by Tukey's multiple comparisons test).
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fig4: Risperidone improves repetitive behavior in Ppar-α mice. Effect of 7–10 days treatment with risperidone (0.01 mg/kg−1, IP) on marble burying behavior (A) and self-grooming (C). Re-appearance of the increased marble burying (B) and self-grooming behaviors (D) one week after treatment's suspension (3 months-old male mice n = 8–12; *p < 0.05 and **p < 0.01 vs wild type mice, &p < 0.05 vs Ppar-α −/− mice treated with vehicle; one-way ANOVA, followed by Tukey's multiple comparisons test).

Mentions: To investigate whether the behavioral alterations observed in Ppar-α −/− are ameliorated by antipsychotic medication, wild type and Ppar-α −/− littermates were treated with risperidone or vehicle for 7–10 days and were then assessed in the marble burying assay, self-grooming in the home cage and MWM tasks. Risperidone (0.01 mg/kg, IP) normalized the behavior of Ppar-α −/− mice in the marble burying test (Figure 4A), and it reversed the elevated self-grooming behavior (Figure 4C). It did not, however, correct the reversal-learning deficit in the MWM (data not shown). Mice were retested 7 days after risperidone was withdrawn, and both marble burying and self-grooming behavior returned to levels similar to those observed in unmedicated mice (Figure 4B, D). Thus, Ppar-α −/− mice exhibit an improved behavioral profile when treated with an antipsychotic medication.


Peroxisome proliferator-activated receptor alpha plays a crucial role in behavioral repetition and cognitive flexibility in mice.

D'Agostino G, Cristiano C, Lyons DJ, Citraro R, Russo E, Avagliano C, Russo R, Raso GM, Meli R, De Sarro G, Heisler LK, Calignano A - Mol Metab (2015)

Risperidone improves repetitive behavior in Ppar-α  mice. Effect of 7–10 days treatment with risperidone (0.01 mg/kg−1, IP) on marble burying behavior (A) and self-grooming (C). Re-appearance of the increased marble burying (B) and self-grooming behaviors (D) one week after treatment's suspension (3 months-old male mice n = 8–12; *p < 0.05 and **p < 0.01 vs wild type mice, &p < 0.05 vs Ppar-α −/− mice treated with vehicle; one-way ANOVA, followed by Tukey's multiple comparisons test).
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4481424&req=5

fig4: Risperidone improves repetitive behavior in Ppar-α mice. Effect of 7–10 days treatment with risperidone (0.01 mg/kg−1, IP) on marble burying behavior (A) and self-grooming (C). Re-appearance of the increased marble burying (B) and self-grooming behaviors (D) one week after treatment's suspension (3 months-old male mice n = 8–12; *p < 0.05 and **p < 0.01 vs wild type mice, &p < 0.05 vs Ppar-α −/− mice treated with vehicle; one-way ANOVA, followed by Tukey's multiple comparisons test).
Mentions: To investigate whether the behavioral alterations observed in Ppar-α −/− are ameliorated by antipsychotic medication, wild type and Ppar-α −/− littermates were treated with risperidone or vehicle for 7–10 days and were then assessed in the marble burying assay, self-grooming in the home cage and MWM tasks. Risperidone (0.01 mg/kg, IP) normalized the behavior of Ppar-α −/− mice in the marble burying test (Figure 4A), and it reversed the elevated self-grooming behavior (Figure 4C). It did not, however, correct the reversal-learning deficit in the MWM (data not shown). Mice were retested 7 days after risperidone was withdrawn, and both marble burying and self-grooming behavior returned to levels similar to those observed in unmedicated mice (Figure 4B, D). Thus, Ppar-α −/− mice exhibit an improved behavioral profile when treated with an antipsychotic medication.

Bottom Line: Specifically, we observed that Ppar-α genetic perturbation promotes rewiring of cortical and hippocampal regions and a behavioral phenotype of cognitive inflexibility, perseveration and blunted responses to psychomimetic drugs.Furthermore, we demonstrate that the antipsychotic and autism spectrum disorder (ASD) medication risperidone ameliorates the behavioral profile of Ppar-α deficient mice.These results thereby reveal an unforeseen therapeutic application for a class of drugs currently in human use.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy ; Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, United Kingdom.

ABSTRACT

Background/objectives: Nuclear peroxisome proliferator activated receptor-α (PPAR-α) plays a fundamental role in the regulation of lipid homeostasis and is the target of medications used to treat dyslipidemia. However, little is known about the role of PPAR-α in mouse behavior.

Methods: To investigate the function of Ppar-α in cognitive functions, a behavioral phenotype analysis of mice with a targeted genetic disruption of Ppar-α was performed in combination with neuroanatomical, biochemical and pharmacological manipulations. The therapeutic exploitability of PPAR-α was probed in mice using a pharmacological model of psychosis and a genetic model (BTBR T + tf/J) exhibiting a high rate of repetitive behavior.

Results: An unexpected role for brain Ppar-α in the regulation of cognitive behavior in mice was revealed. Specifically, we observed that Ppar-α genetic perturbation promotes rewiring of cortical and hippocampal regions and a behavioral phenotype of cognitive inflexibility, perseveration and blunted responses to psychomimetic drugs. Furthermore, we demonstrate that the antipsychotic and autism spectrum disorder (ASD) medication risperidone ameliorates the behavioral profile of Ppar-α deficient mice. Importantly, we reveal that pharmacological PPAR-α agonist treatment in mice improves behavior in a pharmacological model of ketamine-induced behavioral dysinhibition and repetitive behavior in BTBR T + tf/J mice.

Conclusion: Our data indicate that Ppar-α is required for normal cognitive function and that pharmacological stimulation of PPAR-α improves cognitive function in pharmacological and genetic models of impaired cognitive function in mice. These results thereby reveal an unforeseen therapeutic application for a class of drugs currently in human use.

No MeSH data available.


Related in: MedlinePlus